U.S. patent number 6,387,956 [Application Number 09/534,778] was granted by the patent office on 2002-05-14 for methods of treating obsessive-compulsive spectrum disorders.
This patent grant is currently assigned to University of Cincinnati. Invention is credited to Toby D. Goldsmith, Paul E. Keck, Jr., Nathan A. Shapira.
United States Patent |
6,387,956 |
Shapira , et al. |
May 14, 2002 |
**Please see images for:
( Certificate of Correction ) ** |
Methods of treating obsessive-compulsive spectrum disorders
Abstract
A method of treating an obsessive-compulsive spectrum disorder
comprises the step of administering an effective amount of tramadol
to an individual.
Inventors: |
Shapira; Nathan A.
(Gainesville, FL), Goldsmith; Toby D. (Gainesville, FL),
Keck, Jr.; Paul E. (Cincinnati, OH) |
Assignee: |
University of Cincinnati
(Cincinnati, OH)
|
Family
ID: |
26824079 |
Appl.
No.: |
09/534,778 |
Filed: |
March 24, 2000 |
Current U.S.
Class: |
514/646; 424/449;
514/217; 514/321; 514/647; 514/651; 514/654; 514/657 |
Current CPC
Class: |
A61K
31/135 (20130101); A61K 31/15 (20130101); A61K
31/4525 (20130101); A61K 31/55 (20130101); A61K
31/135 (20130101); A61K 31/15 (20130101); A61K
31/4525 (20130101); A61K 31/55 (20130101); A61K
2300/00 (20130101); A61K 2300/00 (20130101); A61K
2300/00 (20130101); A61K 2300/00 (20130101) |
Current International
Class: |
A61K
31/135 (20060101); A61K 31/15 (20060101); A61K
31/4525 (20060101); A61K 31/55 (20060101); A61K
31/4523 (20060101); A61K 031/135 () |
Field of
Search: |
;514/646,217,321,647,651,658,657 ;424/449 |
References Cited
[Referenced By]
U.S. Patent Documents
Other References
Shapira et al., Open-Label Pilot Study of Tramadol Hydrochloride in
Treatment-Refractory Obssessive-Compulsive Disorder; Depression and
Anxiety 6:170-173 (1997). .
Hollander, M.D., Obsessive-Compulsive Disorder: The Hidden
Epidemic; J. Clin Psychiatry; 58(suppl. 12):3-6 (1997). .
Lee, et al., Tramadol: A Preliminary Review of Its Pharmacodynamic
and Pharmacokinetics Properties, and Therapeutic Potential in Acute
and Chronic Pain States; Drugs 46 (2): 313-340 (1993). .
Dayer, et al., The Pharmacology of Tramadol; Drugs 47 (Suppl. 1):
3-7 (1994). .
Goodman, et al., Pharmacotherapy of Obsessive Compulsive Disorder;
J Clin Psychiatry 53:4 (suppl.), pp. 29-37 (Apr. 1992). .
Domingquez, M.D., Serotonergic Antidepressants and Their Efficacy
in Obsessive Compulsive Disorder; J Clin Pyschiatry 53:10 (suppl.),
pp. 56-59 (Oct. 1992). .
Leckman, M.D., "Just Right" Perceptions Associated With Compulsive
Behavior in Tourette's Syndrome; Am J Psychiatry 151:5, pp. 675:680
(May 1994). .
McConville, et al., Sequential use of oploid antagoinists and
agonists in Tourrette'syndrome; The Lancet, vol. 343:601 (Mar. 5,
1994). .
Goodman, M.D., et al., The Yale-Brown Obsessive Compulsive Scale;
Arch Gen Psychiatry--vol. 46: 1006-1011 (Nov. 1989). .
Abstract No. NR 101, "Tramadol for Treatment-Refractory OCD",
Abstracts for 150th Annual Meeting of the American Psychiatric
Association, May 17-22, 1997..
|
Primary Examiner: Krass; Frederick
Attorney, Agent or Firm: Dinsmore & Shohl LLP
Parent Case Text
This application claims the benefit of U.S. Provisional Application
No. 60/125,907, filed Mar. 28, 1999.
Claims
What is claimed is:
1. A method of treating an obsessive-compulsive spectrum disorder,
comprising the step of administering an effective amount of
tramadol to an individual in need thereof.
2. A method according to claim 1, wherein the tramadol is in the
form of a hydrochloride salt.
3. A method according to claim 1, wherein the obsessive-compulsive
spectrum disorder is selected from the group consisting of
obsessive-compulsive disorder, Tourette's syndrome, body dismorphic
disorder, hypochondriasis, eating disorders, impulse control
disorders, paraphilias and nonparaphilic sexual addictions,
Sydeham's chorea, torticollis, autism and combinations thereof.
4. A method according to claim 3, wherein the obsessive-compulsive
spectrum disorder is an impulse control disorder selected from the
group consisting of intermittent explosive disorder, kleptomania,
pathological gambling, pyromania, compulsive shopping, compulsive
buying, repetitive self-mutilation, onychophagia, psychogenic
excoriation, trichotillomania and combinations thereof.
5. A method according to claim 2, wherein the obsessive-compulsive
spectrum disorder is obsessive-compulsive disorder.
6. A method according to claim 1, wherein the individual is
refractory to serotonin reuptake inhibitors.
7. A method according to claim 2, comprising the step of
administering from about 50 to about 400 mg of tramadol
hydrochloride per day to an individual.
8. A method according to claim 7, wherein the total daily amount of
tramadol hydrochloride is administered in from about 2 to about 5
doses.
9. A method according to claim 1, wherein the individual exhibits a
decrease in Yale-Brown Obsessive-Compulsive Scale score after about
fourteen days of treatment.
10. A method according to claim 1, further comprising the step of
administering a serotonin reuptake inhibitor to the individual.
11. A method according to claim 10, wherein the serotonin reuptake
inhibitor is selected from the group consisting of clomipramine,
fluoxetine, fluvoxamine, sertraline, paroxetine and mixtures
thereof.
12. A method according to claim 1, wherein the tramadol is
administered by a transepidermal patch.
13. A method of obtaining a treatment response to an
obsessive-compulsive spectrum disorder in less than fourteen days,
comprising the step of administering an effective amount of
tramadol to an individual in need thereof.
14. A method according to claim 13, wherein the tramadol is in the
form of a hydrochloride salt.
15. A method according to claim 13, wherein the individual exhibits
a decrease in Yale-Brown Obsessive-Compulsive Scale score after
about fourteen days of treatment.
16. A method according to claim 13, wherein the individual exhibits
a decrease in Yale-Brown Obsessive-Compulsive Scale score after
about seven days of treatment.
17. A method according to claim 13, further comprising treating the
individual with behavior modification therapy.
18. A method according to claim 14, comprising the step of
administering from about 50 to about 400 mg of tramadol
hydrochloride per day to the individual.
19. A method according to claim 18, wherein the total daily amount
of tramadol hydrochloride is administered in from about 2 to about
5 doses.
20. A method according to claim 13, further comprising the step of
administering a serotonin reuptake inhibitor to the individual.
21. A method according to claim 20, wherein the serotonin reuptake
inhibitor is selected from the group consisting of clomipramine,
fluoxetine, fluvoxamine, sertraline, paroxetine and mixtures
thereof.
22. A method according to claim 20, comprising orally administering
from about 10 to about 200 mg of a serotonin reuptake inhibitor per
day to the individual.
23. A method according to claim 13, wherein the
obsessive-compulsive spectrum disorder is selected from bulimia
nervosa and binge eating disorder, and further wherein the
individual has a decreased appetite after about 14 days of
treatment.
24. A method of treating an obsessive-compulsive spectrum disorder,
comprising the step of administering an effective amount of
tramadol to and individual in need thereof on an as-needed
basis.
25. A method according to claim 24, wherein the
obsessive-compulsive spectrum disorder is Tourette's syndrome.
26. A method according to claim 25, wherein the tramadol is in the
form of a hydrochloride salt.
27. A method according to claim 26, wherein the step of
administering tramadol hydrochloride comprises orally administering
from about 50 to about 200 mg tramadol hydrochloride.
28. A method according to claim 27, wherein the step of
administering tramadol hydrochloride comprises orally administering
the tramadol hydrochloride at least about one hour prior to the
point in time at which a decrease in Tourette's syndrome symptoms
is desired.
Description
TECHNICAL FIELD
This invention relates to methods of treating obsessive-compulsive
spectrum disorders. More particularly, the invention relates to
methods of treating obsessive-compulsive spectrum disorders
comprising the step of administering an effective amount of
tramadol to an individual.
BACKGROUND ART
Although originally believed to be rare, it is now known that
obsessive-compulsive disorder (OCD) is common, with estimated life
time prevalence rates in the United States ranging from 1.9% to
3.3% (Shapira et al., Depression and Anxiety 6; 170-173 (1997).)
The Diagnostic and Statistical Manual of Mental Disorders, fourth
edition, (DSM-IV), includes as its diagnostic criteria for OCD
that: the person exhibits either obsessions or compulsions; at some
point during the course of the disorder the person has recognized
that the obsessions or compulsions are excessive or unreasonable;
the obsessions or compulsions caused marked stress, are
time-consuming or significantly interfere with the person's normal
routine, occupational/academic functioning, or usual social
activities or relationships; if another axis I disorder is present,
the content of the obsessions or compulsions is not restricted to
it; and the disturbance is not due to the direct physiologic
effects of a substance or a general medical condition.
The DSM-IV sets four indicia of obsessions. First, the person has
recurrent and/or persistent thoughts, impulses or images that are
experienced at some time during the disturbance as intrusive and
inappropriate and as causing marked anxiety or distress. Second,
the thoughts, impulses or images are not simply excessive worries
about real-life problems. Third, the person attempts to ignore or
suppress such thoughts, impulses or images or to neutralize them
through some other thought or action. Fourth, the person recognizes
that the obsessional thoughts, impulses, or images are products of
his or her own mind and are not imposed from without.
The DSM-IV sets forth two indicia of compulsion. First, the person
has repetitive behaviors or mental acts that the person feels
driven to perform in response to an obsession or according to rules
that must be applied rigidly. Repetitive behaviors include hand
washing, ordering and checking, while mental acts include praying,
counting and repeating words silently. Second, the behaviors or
mental acts are aimed at preventing some dreaded event or
situation; however, these behaviors or mental acts either are not
connected in a realistic way to what they are designed to
neutralize or prevent, or are clearly excessive.
Individuals who meet the DSM-IV criteria for OCD can be scored
using the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS). Y-BOCS
scores range from 0 to 40. Generally, 0 to 7 is considered a
subclinical syndrome, 8-15 is considered mild, 16-23 is considered
moderate, 24-31 is considered severe, and 32-40 is considered
extremely severe.
A wide range of psychiatric and neuropsychiatric disorders appear
to be related to OCD and form a family of related disorders
referred to as obsessive-compulsive (OC) spectrum disorders.
Obsessive-compulsive spectrum disorders include somatoform
disorders, eating disorders, impulse control disorders (ICDs),
paraphilia and nonparaphilic sexual addictions, Sydeham's chorea,
torticollis, autism, and movement disorders, including Tourette's
syndrome. As used herein, "obsessive-compulsive spectrum disorders"
is intended to include OCD.
Somatoform disorders include body dysmorphic disorder (BDD) and
hyperchondriasis. Body dysmorphic disorder (BDD) is a preoccupation
with an imagined slight defect in appearance that causes
significant distress or impairment in functioning. Individuals
suffering from BDD have preoccupations similar to OCD obsessions in
that they have repetitive intrusive thoughts, often perform
time-consuming, repetitive and sometimes ritualistic behaviors.
Hypochondriasis is a preoccupation with the fear of having, or the
idea that one has, a serious disease based on the person's
misinterpretation of bodily signs or symptoms. Hypochondriacal
preoccupations resemble OCD obsessions in that they are often
experienced as intrusive and persistent, and the individuals often
display repetitive checking behaviors.
Eating disorders include anorexia nervosa, bulimia nervosa and
binge eating disorder (BED). The DSM-IV defines anorexia nervosa as
a refusal to maintain a minimally normal body weight; intensive
fear of gaining weight or becoming fat even though underweight;
significant disturbance in perception of body shape or size; and,
in females, amenorrhea. The DSM-IV defines bulimia nervosa as
recurrent episodes of binge eating followed by inappropriate
compensatory behaviors designed to prevent a weight gain. BED is
characterized by recurrent episodes of binge eating in the absence
of regular use of inappropriate compensatory behaviors. There is
some overlap among anorexia nervosa, bulimia nervosa, and BED.
However, all three disorders are characterized by a core
preoccupation with food and body weight. Individuals suffering from
eating disorders often perform specific rituals, and have an
abnormal preoccupation with food and weight.
The DSM-IV defines an impulse control disorder (ICD) as the failure
to resist the impulse, drive or temptation to perform some act that
is harmful. ICDs include intermitted explosive disorder (IED),
compulsive buying or shopping, repetitive self-mutilation (RSM),
onychophagia, psychogenic excoriation, kleptomania, pathological
gambling, and trichotillomania. Most individuals suffering from
ICDs experience increasing sense of tension or arousal before
committing the act, then pleasure, gratification or relief at the
time of committing the act. Individuals suffering from ICD often
experience impulses which are intrusive, persistent and associated
with anxiety or tension. Individuals suffering from paraphilias and
nonparaphilic sexual addictions (NPSAs) experience similar
increasing senses of tension or arousal before committing the act,
then pleasure, gratification or relief at the time of committing
the act.
Tourette's syndrome is a chronic neuropsychiatric disorder
characterized by motor tics and one or more vocal tics beginning
before the age of 18 years. The DSM-IV defines a tic as a sudden,
rapid, recurrent, nonrhythmic, stereotyped motor movement or
vocalization. Tourette's syndrome patients may be able to suppress
tics for varying lengths of time, but eventually experience them as
irresistible and perform them. Tourette's patients exhibit
obsessions resembling OCD obsessions, for example, they often feel
the need to perform tics until they are felt to be "just
right."
Autism is characterized by difficulties with social interaction,
speech and communication, and by a compulsive core. Autistic
individuals often display compulsive, repetitive behaviors.
Behavior modification therapy is often efficacious in treating
obsessive-compulsive spectrum disorders, including OCD. However,
behavior modification therapy generally requires prolonged periods
of treatment. Also, an individual may not respond favorably to
behavior modification therapy unless the severe OC spectrum
disorder symptoms are first controlled or decreased. Thus, it is
often desirable to supplement the initial stages of behavior
modification with drug therapy. Preferably, the drug therapy will
be one that has a short onset of action, preferably less than two
weeks.
Some OC spectrum disorders, such a bulimia nervosa, have been shown
to respond to monoamine oxidase inhibitors (MAOIs). Unfortunately,
people who use MAOIs adhere to numerous dietary restrictions and
observe special precautions to avoid drug interactions.
OCD has been treated with serotonin reuptake inhibitors (SRIs) such
as clomipramine, fluoxetine, fluvoxamine, sertraline and
paroxetine. There is also evidence to suggest that Tourette's
syndrome, hypochondriasis, anorexia nervosa, and ICDs such as
intermitted explosive disorder (IED), kleptomania, pathological
gambling, trichotillomania, compulsive shopping, onychophagia and
psychogenic excoriation may respond to SRIs. (Goldsmith et al.,
Conceptual Foundations of Obsessive-Compulsive Spectrum Disorder,
in Obsessive-Compulsive Disorder, Richard P. Swinson et al.
Editors, The Guilford Press. pages 397-425 (1998).) SRIs have also
been used to treat compulsive symptoms in autism. (Hollander, J.
Clim. Psychiatry, 58(12): 3-6 (1997).)
Unfortunately, some individuals are refractory to serotonin
reuptake inhibitors. From approximately 30 to 50% of individuals do
not respond at all to serotonin reuptake inhibitors, while many who
do respond do so only partially. Further, serotonin reuptake
inhibitors have a slow onset of action and often require eight to
ten weeks of treatment to achieve a significant reduction in
symptoms. Also, individuals suffering from movement disorders, such
as Tourette's syndrome, often desire a drug that can be taken pro
re nata (on an as-needed basis).
Thus there is a need for a therapeutic agent for the treatment of
SRI-refractory individuals suffering from obsessive-compulsive
spectrum disorders. Further, there is a need for a pharmacological
agent which has a short onset of action, preferably less than two
weeks. There is an additional need for a drug which can be taken as
needed for tic disorders.
Tramadol ((.+-.)cis-2-[(dimethylamino)methyl]-1(3-methoxyphenyl)
cyclohexanol) and its derivatives, including tramadol salts such as
tramadol hydrochloride ((.+-.)
cis-2-[(dimethylamino)methyl]-1(3-methoxyphenyl)cyclohexanolhydrochloride)
, are synthetic analgesic compounds. It is believed tramadol and
its salts and other derivatives act through two complimentary
mechanisms, one mechanism is binding to mu-opioid receptors and the
other mechanism is weak inhibition of norepinephrine and serotonin
reuptake. Although physicians are often reluctant to prescribe
opioid agonist due to significant abuse potential, tramadol's low
abuse liability, low physical dependence and mild tolerance would
make it a desirable therapeutic alternative to SRIs for individuals
with OC spectrum disorders.
SUMMARY OF THE INVENTION
Accordingly, it is an object of this invention to obviate various
problems of the prior art.
It is an object of this invention to provide novel methods for
treating obsessive-compulsive spectrum disorders.
It is also an object of this invention to treat
obsessive-compulsive spectrum disorders in individuals who are
refractory to selective serotonin reuptake inhibitors.
It is an additional object of this invention to provide methods of
treating obsessive-compulsive spectrum disorders, which methods
provide a rapid onset of response.
It is also an object of this invention to provide a method of
treating obsessive-compulsive spectrum disorders, particularly
Tourette's syndrome, on an as-needed basis.
In accordance with one aspect of the present invention, methods of
treating obsessive-compulsive spectrum disorders comprise
administering an effective amount of tramadol, preferably tramadol
hydrochloride, to an individual.
In accordance with another aspect of the present invention, methods
of obtaining rapid treatment responses for obsessive-compulsive
spectrum disorders comprise administering an effective amount of
tramadol, preferably tramadol hydrochloride, to an individual.
In accordance with another aspect of the present invention, methods
of treating obsessive-compulsive spectrum disorders, particularly
Tourette's syndrome, comprise administering an effective amount of
tramadol, preferably tramadol hydrochloride, to an individual on an
as-needed basis.
It has now been found that tramadol, which is primarily used for
analgesia, can provide efficacious treatment of
obsessive-compulsive spectrum disorders. Tramadol has been found to
provide a rapid response, to be efficacious in serotonin reuptake
inhibitor-refractory individuals, and to be useful in an as-needed
dosing regime for movement disorders.
These and additional objects and advantages will be more fully
apparent in view of the following description.
BRIEF DESCRIPTION OF THE DRAWINGS
While the specification concludes with claims particularly pointing
out and distinctly claiming the present invention, it is believed
the same will be better understood from the following description
taken in conjunction with the accompanying drawings in which:
FIG. 1 is a graphical representation of the weekly mean .+-.
standard deviation of weight and tramadol doses for seven patients.
The first columns in each of weeks 1-6 represent weight in pounds
while the second columns represent total daily tramadol
hydrochloride dose in milligrams.
FIGS. 2-8 are graphical representations of the weekly weight and
tramadol dose for the individual patients. In each of FIGS. 2-8,
Series 1 represents total daily tramadol hydrochloride dose weight
while Series 2 refers to weight in pounds.
DETAILED DESCRIPTION
Applicants have found that tramadol, which is primarily used as an
analgesic, provides therapeutic benefits for individuals with
obsessive-compulsive (OC) spectrum disorders, including
obsessive-compulsive disorder. Tramadol has been found to be
particularly useful in treating individuals which are refractory to
serotonin reuptake inhibitors (SRIs). Applicants have also found a
surprisingly rapid onset of response in tramadol-treated
individuals as compared to SRI-treated individuals, and have also
found that it is possible to treat OC spectrum disorder symptoms on
an as-needed basis with tramadol.
As used herein, "obsessive-compulsive spectrum disorders" is
intended to include obsessive-compulsive disorder (OCD), somatoform
disorders, eating disorders, impulse control disorders, paraphilias
and nonparaphilic sexual addictions, Sydeham's chorea, torticollis,
autism, and movement disorders. Somatoform disorders include body
dysmorphic disorder (BDD) and hypochondriasis; eating disorders
include anorexia nervosa, bulimia nervosa and binge-eating disorder
(BED); impulse control disorders (ICDs) include intermittent
explosive disorder (IED), kleptomania, pathological gambling,
pyromania, compulsive buying or shopping, repetitive
self-mutilation (RSM), onychophagia, psychogenic excoriation;
trichotillomania; and movement disorders include Tourette's
syndrome.
As used herein, "serotonin reuptake inhibitors" is intended to
refer to drugs other than tramadol which have the capability of
inhibiting the reuptake of the neurotransmitter serotonin.
Serotonin reuptake inhibitors (SRIs) include clomipramine, and
compounds considered to be selective serotonin reuptake inhibitors
(SSRIs) such as fluoxetine, fluvoxamine, sertraline, and
paroxetine. Clomipramine is a tricyclic antidepressant believed to
influence obsessive and compulsive behaviors through its capacity
to inhibit the reuptake of serotonin. Unfortunately, tricyclic
antidepressants often cause sedation, weight gain, and
anticholinergic effects such as increased heart rate, decreased
blood pressure upon standing, blurred vision and confusion.
Generally SSRIs such as fluoxetine, fluvoxamine, sertraline and
paroxetine are preferred as they have fewer adverse side
effects.
The severity of the obsessive-compulsive spectrum disorders, and
particularly OCD, is evaluated using the Yale-Brown
Obsessive-Compulsive Scale (Y-BOCS). The Y-BOCS assigns numerical
value to categories such as the amount of time spent on,
interference from, distress from, resistance to, and control over
obsession and compulsions. Y-BOCS scores range from 0-40, with 0-7
being subclinical, 8-l5 being mild, 16-23 being moderate, 24-31
being severe, and 32-40 being extreme severity. Individuals with
moderate to extremely severe obsessive-compulsive spectrum
disorders generally have symptoms which interfere with their daily
activities.
The treatment methods of the present invention comprise
administering an effective amount of tramadol to an individual. As
used herein, "tramadol" refers to tramadol and its physiologically
acceptable derivatives, such as tramadol salts. A preferred form of
tramadol is tramadol hydrochloride
((.+-.)cis-2[(dimethylamino)methyl]-1-(3-methoxyphenyl)
cyclohexanol hydrochloride), although other salts or
physiologically acceptable forms of tramadol may be employed as
well. Treatment with tramadol is an effective means of treating
individuals who are refractory to selective serotonin reuptake
inhibitors. Further, tramadol is found to have had a rapid onset of
response. Thus, tramadol is particularly preferred for individuals
exhibiting severe and extremely severe forms of OC spectrum
disorders.
The tramadol may be administered in any suitable form, including
tablets, liquids, timed release capsules, in the form of a candy
such as a lollipop, sprinkles which are mixed with soft foods,
sublingual dosing, transepidermal patches, subcutaneous sustained
release devices, nasal sprays, rectal suppositories and injections.
When a sustained release is desired preferred forms are timed
capsules, transepidermal patches, and subcutaneous sustained
release devices. When a quick response is desired preferred forms
are sublingual dosing and injection. For children, geriatric
patients, and patients who might have trouble swallowing or
compliance problems, preferred forms are candy, sprinkles, rectal
suppositories and liquids.
As used herein, "an effective amount" refers to the minimum amount
required to decrease the severity of the OC spectrum disorder
symptoms. An individual preferably exhibits a decrease in Y-BOCS
scores after about 14 days of treatment, more preferably after
about 7 days of treatment. Even more preferably, the individual
experiences a decrease in compulsive behavior after about 2 days of
treatment.
Preferably the tramadol is in the form of a hydrochloride.
Generally, the individual is treated with a total of from about 50
to about 400, preferably from about 100 to about 400, mg of
tramadol per day. In one embodiment, the tramadol dose may be
divided into from about 2 to about 5, preferably from about 2 to
about 3, individual doses a day, with each individual dose being
from about 50 to about 200, more preferably from about 50 to about
100, mg of tramadol. In one embodiment the individual is treated
with from about 50 to about 100 mg of tramadol two to three times a
day. Generally two to three individual doses a day are preferred
from efficacy, tolerability and compliance aspects, however, more
severely affected individuals may require from four to five
individual doses a day to control symptoms.
Alternatively, the tramadol may be administered pro re nata (on an
as-needed basis). Preferably the tramadol is administered orally or
sublingually.
Many individuals suffering from OC spectrum disorders respond
favorably to behavior modification therapy. However, with some
individuals the OC spectrum disorder symptoms may be so severe that
they interfere with the initiation of behavior modification
therapy. For example, an individual with extremely severe OCD
directed toward contamination may be reluctant to leave his
domicile in order to obtain behavior modification therapy. Such an
individual would benefit from a drug therapy which was able to
quickly control or decrease the severity of the OCD symptoms,
thereby rendering the individual more willing to obtain behavior
modification therapy. The rapid onset of response to tramadol
allows for an individual's OC spectrum disorder symptoms would
provide such a benefit. The tramadol treatment may be initiated
prior to or along with the initiation of behavior modification
therapy. Individuals who have already initiated behavior
modification therapy may also be treated with tramadol. This may be
particularly beneficial if it appears the severity of the OC
spectrum disorder symptoms is interfering with the behavior
modification therapy.
In one preferred embodiment, the individual suffering from an OC
spectrum disorder is treated with tramadol during or prior to
initiation of behavior modification therapy. Preferably, the
tramadol therapy is initiated prior to the initiation of the
behavior modification therapy, more preferably at least about 2
days prior to the initiation of the behavior modification therapy,
even more preferably at least about 7 days prior to the initiation
of the behavior modification therapy. Suitable forms of behavior
modification therapy are known in the art, and include exposure and
response prevention, thought stopping, saturation therapy, stimulus
control therapy, or modeling therapy.
Another surprising advantage of the rapid onset of response of
tramadol is the treatment of the symptoms of OC spectrum disorders,
particularly Tourette's syndrome, on an as-needed basis. As used
herein, "as-needed basis" is intended to refer to a dosing regime
wherein the individual takes a pharmacological agent at a time and
at a level sufficient to control symptoms as desired. Although
tramadol may be prescribed according to a schedule, such as, for
example, 100 mg 4 times a day, there may be occasions when an
as-needed basis is preferred.
For example, an individual with an OC spectrum disorder may desire
to control or decrease symptoms for specific events or occasions. A
Tourette's syndrome patient may wish to take tramadol prior to an
event such as taking a class or giving a speech, while a bulimia
nervosa or BED patient may wish to take tramadol before meals or
particular situations which usually lead to binge eating or
purging. An individual with compulsive buying may take tramadol
before going near stores while an individual with pathologic
gambling may take tramadol before exposures to triggers that lead
to gambling. OCD patients may wish to take an as-needed dose of
tramadol before exposure to a stress-inducing situation. For
example, a patient with contamination obsessions and/or cleaning
compulsions may take tramadol prior to cleaning a bathroom, while a
patient with obsessions of harm may take tramadol prior to caring
for children.
Oral administration of an effective dose of tramadol, preferably
tramadol hydrochloride, at least about one hour prior to the point
in time at which the decrease of symptoms is desired will result in
an effective decrease in symptoms. The tramadol will decrease the
symptoms for a period of up to about six hours. Generally, the
as-needed dose will be from about 50 to about 400 mg of oral
tramadol, preferably tramadol hydrochloride.
Tramadol offers an additional benefit for treatment of impulse
control disorders involving eating, particularly of bulimia nervosa
or BED. It has now been found that tramadol treatment may result in
appetite loss. Thus, individuals treated for bulimia nervosa or BED
would benefit not only by the control of the obsessive and
compulsive symptoms of the disorder, but also by the decrease in
appetite and the resulting weight loss which is likely to occur.
Thus, in one embodiment an individual suffering from bulimia
nervosa or BED is treated with tramadol, preferably tramadol
hydrochloride, at a total daily dose of from about 50 to about 400,
preferably from about 100 to about 400, mg. The individual
generally experiences a decreased appetite after about 14,
preferably after about 7, days of treatment.
If desired, the tramadol treatment may be supplemented with a SRI,
provided the individual responds at least partially to SRIs.
Preferably the SRI is selected from clomipramine, fluvoxamine,
fluoxetine, sertraline, and paroxetine, more preferably, the SRI is
a SSRI selected from the group consisting of fluvoxamine,
fluoxetine, sertraline and paroxetine. Generally, the average dose
of the serotonin reuptake inhibitor is from the range of from about
10 to about 200, more preferably from about 10 to about 40, mg
daily. Preferably the SRI is administered orally.
If long-term maintenance therapy on SRIs are desired, the
individual may initially be treated with a combination of SRI and
tramadol in order to obtain a rapid decrease in the OC spectrum
disorder symptoms. After sufficient time has passed for the SRI
response to occur, generally from about 8 to 10 weeks, the level of
tramadol may be slowly tapered off until the individual is being
treated only with the SRI.
Non-limiting examples of tramadol treatment for
obsessive-compulsive spectrum disorders are set forth below.
EXAMPLE 1
Seven SRI-refractory patients who met the DSM-IV criteria for OCD
for at least six months, who had a minimum score of 15 on the
Y-BOCS, and who had SRI-treatment refractory OCD, as defined as
having an inadequate response to an 8 week therapeutic dose of at
least one SRI, were recruited for a clinical study. Exclusion
criteria for the study included a life-time DSM-IV diagnosis of
mania, psychotic disorder, alcohol or substance abuse or
dependence, prior history of hypersensitivity to tramadol or any
other opioid, a history of seizures, including childhood febrile
seizures, and any clinically relevant abnormal laboratory results
or clinically unstable medical conditions. The 7 patients had a
mean duration of illness of 27.4.+-.9.5 years, and mean previously
failed SRI trials of 2.9.+-.2.1. The patients were not concurrently
receiving behavioral therapy.
Patients were evaluated using the Yale-Brown Obsessive Compulsive
Scale (Y-BOCS), the Hamilton Rating Scale for Depression (HAM-D)
and the Clinical Global Impression Scale (CGI). Subsequent to
screening, the individuals received a six week treatment with
tramadol hydrochloride. The tramadol hydrochloride was initially
administered at 50 mg four times a day for the first week. If there
was less than a 20% drop in baseline Y-BOCS scores by the end of
week one, the tramadol hydrochloride dose was advanced slowly over
1 to 2 weeks to a maximum of 400 mg per day in 3 to 5 divided
doses. Weekly measurements with the Y-BOCS, HAM-D and CGI were used
to assess responses. Y-BOCS and HAM-D values at the start and end
of the trial were compared using the Wilcoxon signed-ranks test.
One patient elected to discontinue medication during week 1 due to
nausea and exacerbation of trichotillomania, while another patient
discontinued medication during week 6 after experiencing a panic
attack.
The mean .+-. standard deviation dose of tramadol hydrochloride for
the six patients completing at least two weeks was 254.+-.119
mg/day (divided into from 3 to 5 doses). The mean .+-. standard
deviation of baseline and endpoint Y-BOCS, HAM-D and severity of
illness CGI and global improvement CGI are set forth below in Table
1. For severity of illness CGI, 4=moderately ill, 5=markedly ill,
and 6=severely ill, while for global improvement CGI, 2=much
improved, 3=minimally improved, 4=no change, 5=minimally worse, and
6=much worse. The scores for the patient who dropped out in week 6
were carried forward from week 5.
TABLE 1 Outcome Measurement Scores at Baseline and Endpoint
Treatments for Six Patients Completing at Least Two Weeks of
Tramadol Hydrochloride Treatment SCALE BASELINE ENDPOINT Y-BOCS,
mean .+-. SD 27.8 .+-. 4.6 20.7* .+-. 5.7 HAM-D, mean .+-. SD 27.7
.+-. 15.9 28.8 .+-. 9.8 Severity of Illness CGI, mean .+-. SD 5.3
.+-. 1.5 4.5 .+-. 1.2 Global Improvement CGI, mean .+-. SD 5.2 .+-.
0.8 2.3 .+-. 1.0 *Z = 2, df = 1, P < 0.05
During tramadol hydrochloride treatment the Y-BOCS scores decreased
while there was no significant change in HAM-D scores. While not
being bound by theory, it is believed that tramadol hydrochloride
may be effecting the symptoms of OCD in SRI treatment refractory
patients via different mechanisms than inhibition of serotonin
reuptake. Three of the seven patients displayed a large decrease
(greater than 6 point) in their Y-BOCS scores within the first
week, indicating a rapid onset of response.
Patients reported that although obsessions persisted in a muted
form, the urges or pressures to perform the compulsions were
diminished. The change in compulsive symptoms was particularly
pronounced in the patients exhibiting a rapid response (a greater
than 6 point drop in Y-BOCS scores within the first week). Two
individuals reported alleviation in compulsive urges after the
first 50 mg dose of tramadol hydrochloride.
The patients reported decreased appetite, and on average lost 5.86
pounds. Weekly mean .+-. standard deviation of weight and tramadol
doses for the patients are set forth below in Table 2, while
weights and tramadol hydrochloride doses for individual patients
are set forth in Table 3. For data analysis purposes, when an
individual's weight was not available, the weight from the previous
week was carried forward.
TABLE 2 Weight and Tramadol Hydrochloride Dose for Seven Patients
Weight, Tramadol Hydrochloride, mean .+-. SD mean .+-. SD Visit
(lbs) (mg/day) Baseline 173.36 .+-. 29.58 0 .+-. 0 Week 1 172.46
.+-. 29.9 157.14 .+-. 60.75 Week 2 170.39 .+-. 29.1 221.43 .+-.
118.52 Week 3 170.5 .+-. 29.64 242.86 .+-. 97.59 Week 4 169.46 .+-.
28.62 257.14 .+-. 83.8 Week 5 169.1 .+-. 28 264.29 .+-. 98.8 Week 6
167.5 .+-. 26.54 253.57 .+-. 115.86
TABLE 2 Weight and Tramadol Hydrochloride Dose for Seven Patients
Weight, Tramadol Hydrochloride, mean .+-. SD mean .+-. SD Visit
(lbs) (mg/day) Baseline 173.36 .+-. 29.58 0 .+-. 0 Week 1 172.46
.+-. 29.9 157.14 .+-. 60.75 Week 2 170.39 .+-. 29.1 221.43 .+-.
118.52 Week 3 170.5 .+-. 29.64 242.86 .+-. 97.59 Week 4 169.46 .+-.
28.62 257.14 .+-. 83.8 Week 5 169.1 .+-. 28 264.29 .+-. 98.8 Week 6
167.5 .+-. 26.54 253.57 .+-. 115.86
At the end of six weeks, 3 patients chose to continue on tramadol
hydrochloride, one chose to discontinue tramadol hydrochloride and
switch to another pharmacologic agent, and three (including the
individuals who dropped out of the study early) discontinued
tramadol hydrochloride without starting another agent. Tramadol
hydrochloride withdrawal Y-BOCS scores were followed for two weeks
for the 3 patients stopping tramadol hydrochloride without adding
another pharmacological agent, and were found to increase from an
average of 14.3 to 19.7.
EXAMPLE 2
A 27 year old female with a ten year history of OCD showed a
worsening of symptoms after the birth of her child. Prior to
tramadol hydrochloride treatment the patient had a Y-BOCS score of
26. Within 24 hours of being placed on a tramadol hydrochloride
treatment of 50 mg twice a day, the patient reported a decrease in
obsessions and compulsions. Thus, the patient showed a rapid
therapeutic response to the tramadol hydrochloride within the first
24 hours.
After one week of tramadol hydrochloride treatment the patient's
Y-BOCS score had decreased to 19. The tramadol hydrochloride
therapy was then supplemented with 20 mg per day of fluoxetine, and
three weeks later the fluoxetine was increased to 40 mg daily.
During the first month of treatment, the patient required up to 350
mg of tramadol hydrochloride daily in divided doses as needed to
diminish her OCD symptoms (generally from 50 to 100 mg 4 times a
day). The dose of tramadol hydrochloride was increased by
approximately 50 to 100 mg weekly over the first three weeks due to
the tolerance to anti-obsessive effects. Six weeks after the
initiation of the combination of tramadol hydrochloride and
fluoxetine, the patient's Y-BOCS scores had decreased to 10, and
the patient found she no longer required the tramadol
hydrochloride.
EXAMPLE 3
A female OCD patient was treated with tramadol hydrochloride for a
total of 11 months, during the last month of the study the patient
was titrated off the tramadol hydrochloride. The only additional
prescribed medication was alendronic acid
((4-amino-1-hydroxybutylidene)bisphosphonic acid) started at week 6
for osteoporosis unrelated to tramadol use. (The patient has a
family history of osteoporosis and previous steroid use.) The
patient's weight and tramadol hydrochloride doses are set forth in
Table 4 below.
TABLE 4 Effect of Tramadol Hydrochloride on Weight Tramadol Weight
Hydrochloride Visit (lbs) (total mg/day) Baseline 129.5 0 Week 1
Not Available 200 Week 2 128.25 300 Week 3 127.0 400 Week 4 127.25
400 Week 5 Not Available 400 Week 6 126.0 300 Week 7 126.3 300 Week
8 126.0 300 Month 3 127.0 350 mg/day for 2 weeks, followed by 400
mg/day Month 4 124.5 400 Month 5 124.75 400 Month 6* 124.5 400
Month 7 127.0 400 Month 8 125.0 400 Month 9 128.0 300 Month 10
127.5 150 Month 11 131.5 100 mg/day for 2 weeks, followed by 50
mg/day for 1 week, then discontinued *Alendronic acid started
As indicated by the data in Table 4, the patient lost weight during
the tramadol hydrochloride treatment, however, the weight was
regained after the tramadol hydrochloride treatment was
discontinued.
EXAMPLE 4
A 45 year old male patient with a history of recurrent major
depressant disorder was treated with extended release bupropion
(1-(3-chlorophenyl)-2-[(1,1-dimethylethyl)amino]-1-propane), at a
total dose of 300 mg per day (200 mg in the morning and 100 mg in
the evening). The patient had a long history of motor and vocal
tics, and the motor tics were found to worsen while patient was
taking bupropion. The patient also reported a history of purging.
The patient exhibited no suicidal ideation or homicidal ideation,
and exhibited no manic symptoms while on the bupropion. It was
determined the patient did not suffer from bipolar affective
disorder or psychosis. The patient was diagnosed as having major
depressant disorder and Tourette's syndrome.
The bupropion was supplemented with 50 mg twice a day of tramadol.
After about two weeks the patient reported no major change in level
of depression, suggesting tramadol itself has no immediate effect
on depression. However, the patient did report that taking 50 mg
tramadol twice a day reduced the number of motor tics without any
side effects. The patient estimated that the number of tics was
reduced by about two-thirds after starting the tramadol. The
patient's bupropion dose was increased to 400 mg per day (200 mg
twice a day), while the tramadol dose was maintained at 50 mg twice
a day. The patient was informed the tramadol dose could be
increased to 50 mg four times a day if the number of tics
increased.
Additional embodiments and modifications within the scope of the
claimed invention will be apparent to one of ordinary skill in the
art. Accordingly, the scope of the present invention shall be
considered in terms of the following claims, and is understood not
to be limited to the details of the methods and examples described
in this specification.
* * * * *